PT  - JOURNAL ARTICLE
AU  - Clark, L. N.
AU  - Ross, B. M.
AU  - Wang, Y.
AU  - Mejia-Santana, H.
AU  - Harris, J.
AU  - Louis, E. D.
AU  - Cote, L. J.
AU  - Andrews, H.
AU  - Fahn, S.
AU  - Waters, C.
AU  - Ford, B.
AU  - Frucht, S.
AU  - Ottman, R.
AU  - Marder, K.
TI  - Mutations in the glucocerebrosidase gene are associated with early-onset Parkinson disease
AID  - 10.1212/01.wnl.0000276989.17578.02
DP  - 2007 Sep 18
TA  - Neurology
PG  - 1270--1277
VI  - 69
IP  - 12
4099  - http://n.neurology.org/content/69/12/1270.short
4100  - http://n.neurology.org/content/69/12/1270.full
SO  - Neurology2007 Sep 18; 69
AB  - Objective: To evaluate the frequency of glucocerebrosidase (GBA) mutations in cases and controls enrolled in the Genetic Epidemiology of Parkinson’s Disease (GEPD) study. Methods: We sequenced all exons of the GBA gene in 278 Parkinson disease (PD) cases and 179 controls enrolled in GEPD, with a wide range of age at onset (AAO), and that included a subset of 178 Jewish cases and 85 Jewish controls. Cases and controls were recruited without knowledge of family history of PD, and cases were oversampled in the AAO < 50 years category. Results: 13.7% of PD cases (38/278) carried GBA mutations, compared with 4.5% of controls (8/179) (odds ratio [OR] 3.4, 95% CI 1.5 to 7.4). The frequency of GBA mutations was 22.2% in 90 cases with AAO ≤ 50 years, compared with 9.7% in 185 cases with AAO > 50 years (OR 2.7, 95% CI 1.3 to 5.3). Adjusting for age at the time of evaluation, sex, family history of PD, and Jewish ancestry, GBA carriers had a 1.7-year-earlier AAO of PD (95% CI 0.5 to 3.3, p < 0.04) than noncarriers. The average AAO of PD was 2.5 years earlier in carriers with an AAO ≤ 50 years compared with noncarriers (95% CI 0.6 to 4.5, p < 0.01) and this was not seen in the AAO > 50 years group. The frequency of GBA mutations was higher in a subset of 178 cases that reported four Jewish grandparents (16.9%) than in cases who did not report Jewish ancestry (8.0%) (p < 0.01). Nine different GBA mutations were identified in PD cases, including 84insGG, E326K, T369M, N370S, D409H, R496H, L444P, RecNciI, and a novel mutation, P175P. Conclusions: This study suggests that the Glucocerebrosidase gene may be a susceptibility gene for Parkinson disease and that Glucocerebrosidase mutations may modify age at onset. GLOSSARY: AAO = age at onset; cDNA = complementary DNA; GBA = glucocerebrosidase; GD = Gaucher disease; GEPD = Genetic Epidemiology of Parkinson’s Disease; MMSE = Mini-Mental State Examination; NA = not applicable; DLB = dementia with Lewy bodies; OR = odds ratio; PD = Parkinson disease; SNP = single nucleotide polymorphism; UPDRS = Unified Parkinson’s Disease Rating Scale.